Project Summary/Abstract Kidney transplant extends life, improves quality of life, and reduces healthcare costs. Unfortunately, the waiting list exceeds 100,000 people while only 13,000 deceased donor kidney transplants occur annually and many patients wait >5 years for a deceased donor transplant. Yet, over 800 kidneys from donors with hepatitis C virus (HCV) were discarded in 2016; hundreds more kidneys are never procured because of the perception that no center will accept them. The reluctance to transplant HCV-infected organs stems from studies showing elevated rates of new-onset diabetes after transplant and cardiovascular disease associated with HCV. Yet, new direct acting antivirals with cure rates of >95% and few side effects have transformed HCV treatment and prompted some transplant leaders to view discarded HCV-infected organs as a valuable opportunity for waitlisted patients with and without pre-existing HCV. It is unknown whether DAA treatment will fully mitigate the risks related to donor-derived HCV. Because of this uncertainty, transplant leaders have highlighted the need for high quality trials to assess outcomes when HCV-infected kidneys are transplanted into HCV-negative recipients. In the pilot THINKER-1 and THINKER-2 trials, we implemented a rigorous informed consent process and transplanted 20 HCV-negative patients with kidneys from HCV-infected donors. Six months post- transplant, all have good allograft function and HCV cure after antiviral treatment. The preliminary results of these pilot trials form a strong rationale for a multicenter trial. The overarching goal of the proposed trial is to determine if kidneys from HCV-infected donors can safely be transplanted into HCV-negative patients with end-stage renal disease. The aim of this U34 grant is to finalize the trial design and make major progress on important operational and regulatory milestones. We will refine the protocol, write the manual of operations, and fully define recruitment procedures with the NIDDK. The data coordinating center will complete the: a) data management plan; b) data collection procedures; c) procedures and documents for informed consent; and d) a data management system. The procedures for centralized HCV genotyping and nucleic acid testing, as well as central measurement of HbA1c and glycated albumin, will be finalized. All eight sites will have IRB approval and requisite training to begin enrolling transplant candidates into the trial. The subsequent U-01 will have the following aims: 1) To estimate the HCV cure rate after transplant using kidneys from HCV-infected deceased donors for HCV-negative recipients, followed by treatment with direct acting antiviral therapy; 2) To determine if one-year allograft function is non-inferior for HCV-negative patients transplanted with a kidney from an HCV-infected donor (vs. an HCV-negative kidney); 3) To determine if the risk of new-onset diabetes after transplant (NODAT) is not increased among patients transplanted with an HCV-infected kidney (vs HCV- negative kidney), and 4) To determine whether consenting to being transplanted with a kidney from an HCV- infected donor is associated with a superior survival vs. waiting for an HCV-negative kidney.